Etravirine is chemically, 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile and has the structural formula:

Etravirine is a drug used for the treatment of HIV. Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTIs). Unlike the currently available agents in the class, resistance to other NNRTIs does not seem to confer resistance to etravirine. Etravirine is marketed under the brand name Intelence® by Tibotec.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Etravirine can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
Etravirine and its salts were described in U.S. Pat. No. 7,037,917. According to the patent also described a process for the preparation of etravirine which comprises treating 4-[[6-chloro-5-bromo-2[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile with ammonia.
Process for the preparation of etravirine was described in Drugs of the Future 2005, 30(5): 462-468. According to the process of etravirine which comprises treating 4-[[6-chloro-5-bromo-2[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzo-nitrile with ammonia.
Process for the preparation of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile was described in Organic process research & development., 2010, 14(3); 657-660. According to the process of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile which comprises reacting 4-aminobenzonitrile in N-methylpyrrolidone with 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethylbenzonitrile in the presence of potassium tert-butoxide.
Process for the preparation of etravirine was described in Organic process research & development., 2010, 14(3); 657-660. According to the publication, crystalline solid of etravirine was obtained by dissolving crude etravirine in acetone at 50 to 55° C. and was treated with activated charcoal, and isolating. The crystalline etravirine obtained by the process of the prior art is herein after designated as etravirine crystalline form I. The powdered x-ray diffractogram (PXRD) of etravirine crystalline Form I is shown in FIG. 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2θ angle positions at about 8.7, 9.1, 13.0, 19.4, 19.6, 23.5, 26.5, 26.8 and 28.5±0.2 degrees.
We have discovered novel process for the preparation of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile is a key intermediate for the preparation of etravirine.
We have also discovered a process for the preparation of consistently reproducible etravirine crystalline form I.
We have also discovered that etravirine can be prepared in two well-defined and consistently reproducible crystalline forms.
Thus, one object of the present invention is to provide a process for the preparation of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile.
Another object of the present invention is to provide a process for the preparation of etravirine crystalline form I.
Yet another object of the present invention is to provide novel crystalline forms of etravirine, process for their preparation and pharmaceutical compositions comprising them.